Nlrp3 inflammasome activation and Gasdermin D-driven pyroptosis are immunopathogenic upon gastrointestinal norovirus infection
| Autor: | Liesbet Martens, Mohamed Lamkanfi, Andy Wullaert, Soroush T Sarvestani, Jason M. Mackenzie, Frédéric Sorgeloos, Ian Goodfellow, Yvan Saeys, Geert van Loo, Hanne Dubois |
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| Přispěvatelé: | Dubois, Hanne [0000-0003-4699-5405], Sorgeloos, Frederic [0000-0002-6492-8524], Martens, Liesbet [0000-0001-9180-7456], van Loo, Geert [0000-0002-8427-4775], Wullaert, Andy [0000-0001-5012-654X], Apollo - University of Cambridge Repository |
| Rok vydání: | 2019 |
| Předmět: |
RNA viruses
Viral Diseases Inflammasomes Physiology Interleukin-1beta ved/biology.organism_classification_rank.species PROTEIN Apoptosis Pathology and Laboratory Medicine Biochemistry Mice White Blood Cells Animal Cells Medicine and Health Sciences Gastrointestinal Infections Biology (General) Immune Response Cells Cultured Caliciviridae Infections Mice Knockout 0303 health sciences Immune System Proteins Cell Death integumentary system 030302 biochemistry & molecular biology Intracellular Signaling Peptides and Proteins Pyroptosis Inflammasome APOPTOSIS 3. Good health STAT1 Transcription Factor Infectious Diseases Cell Processes Medical Microbiology Viral Pathogens Viruses VIRUS Cellular Types Pathogens medicine.symptom Research Article medicine.drug QH301-705.5 Immune Cells Necroptosis Immunology Caspase 1 Inflammation Gastroenterology and Hepatology Biology Microbiology Caliciviruses 03 medical and health sciences Immune system Virology NLR Family Pyrin Domain-Containing 3 Protein Genetics medicine Animals NECROPTOSIS Microbial Pathogens Molecular Biology Secretion CASPASE-1 030304 developmental biology RELEASE Blood Cells Innate immune system ved/biology Macrophages Norovirus Organisms Proteins Calicivirus Infection Biology and Life Sciences PATHWAYS Cell Biology Phosphate-Binding Proteins RC581-607 Gastrointestinal Tract Mice Inbred C57BL MURINE NOROVIRUS INNATE IMMUNITY Parasitology GSDMD Immunologic diseases. Allergy Apoptosis Regulatory Proteins Physiological Processes Murine norovirus |
| Zdroj: | PLoS Pathogens, Vol 15, Iss 4, p e1007709 (2019) PLOS PATHOGENS PLoS Pathogens |
| ISSN: | 1553-7374 1553-7366 |
| Popis: | Norovirus infection is the leading cause of food-borne gastroenteritis worldwide, being responsible for over 200,000 deaths annually. Studies with murine norovirus (MNV) showed that protective STAT1 signaling controls viral replication and pathogenesis, but the immune mechanisms that noroviruses exploit to induce pathology are elusive. Here, we show that gastrointestinal MNV infection leads to widespread IL-1β maturation in MNV-susceptible STAT1-deficient mice. MNV activates the canonical Nlrp3 inflammasome in macrophages, leading to maturation of IL-1β and to Gasdermin D (GSDMD)-dependent pyroptosis. STAT1-deficient macrophages displayed increased MAVS-mediated expression of pro-IL-1β, facilitating elevated Nlrp3-dependent release of mature IL-1β upon MNV infection. Accordingly, MNV-infected Stat1-/- mice showed Nlrp3-dependent maturation of IL-1β as well as Nlrp3-dependent pyroptosis as assessed by in vivo cleavage of GSDMD to its active N-terminal fragment. While MNV-induced diarrheic responses were not affected, Stat1-/- mice additionally lacking either Nlrp3 or GSDMD displayed lower levels of the fecal inflammatory marker Lipocalin-2 as well as delayed lethality after gastrointestinal MNV infection. Together, these results uncover new insights into the mechanisms of norovirus-induced inflammation and cell death, thereby revealing Nlrp3 inflammasome activation and ensuing GSDMD-driven pyroptosis as contributors to MNV-induced immunopathology in susceptible STAT1-deficient mice. Author summary Gastrointestinal norovirus infections form a serious socio-economic worldwide problem, with about 684 million cases annually worldwide and mortality occurring both in underdeveloped countries and in immunocompromised patients. Despite the urgent global need, no specific treatments are available for norovirus induced gastroenteritis, partly because innate immune responses upon gastrointestinal norovirus infection are largely unresolved. Using the murine norovirus (MNV) model we showed that MNV infection in macrophages leads to a lytic form of cell death termed pyroptosis as well as to the maturation and release of the pro-inflammatory cytokine IL-1β. Maturation of IL-1β was observed also in vivo, after gastrointestinal infection of MNV-susceptible Stat1 knockout mice. We found that these innate immune responses upon MNV infection crucially depended on activation of the Nlrp3 inflammasome leading to Gasdermin D-driven pyroptosis, and inactivating this signaling pathway delayed lethality of MNV-susceptible STAT1 knockout mice after gastrointestinal MNV infection. We thus identified Nlrp3 inflammasome activation and ensuing pyroptosis as a signaling pathway contributing to norovirus-induced immunopathology. Taken together, this study resulted in a more detailed understanding of MNV-induced inflammatory and cell death pathways and provided insights into how gastrointestinal viruses induce immunopathology. |
| Databáze: | OpenAIRE |
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